1. Field of the Invention
This invention relates to certain compounds which antagonize the actions of the neuropeptides cholecystokinin (hereinafter CCK) and gastrin.
CCK and gastrin are peptides, endogenous in human and other species, which regulate biological functions in tissues in the GI tract and central nervous system (CNS). Gastrin and CCK regulate biological activity by acting as autocrine, parocrine, endocrine or neurocrine agents.
The first and principal form of gastrin isolated was the 17 amino acid residue peptide, G-17 or little gastrin. The second major molecular form of gastrin is the 34 amino acid residue peptide, G-34 or big gastrin. G-34 is considered the proform of G-17, but both forms of gastrin are biologically active and nearly equipotent. The smallest residue possessing full biological activity is G-4 which is the final 4 amino acids at the carboxy terminal. Sulfation of the tyrosine residue (6-amino acids from the C-terminal) is not necessary for expression of the bioactivity of gastrin and its congeners.
The major physiologic action of gastrin is the stimulation of acid secretion from the stomach. Gastrin stimulates acid secretion by at least three separate actions: direct stimulation of parietal cell activity; potentiating the actions of histamine, a paracrine stimulus; and by direct release of histamine.
Gastrin is a trophic hormone for gastric, fundic and intestinal mucosa and for the pancreas. Gastrin directly stimulates those biochemical processes, DNA and RNA synthesis, that are involved in tissue growth.
Gastrin also stimulates pepsin secretion and increases gastric mucosal blood flow. It causes electrolyte and water secretion by the stomach, pancreas, liver, and Brunner's glands.
Other possible actions of gastrin may involve the regulation of lower esophageal sphincter contraction and other smooth muscle contractions (motility) in the GI tract.
CCK is a linear amino acid polypeptide that occurs in several bioactive molecular forms: CCK-8, CCK-22, CCK-33, CCK-39 and CCK-58 are the major forms which have been reported. All of the CCK variants require the sulfation of the tyrosine residue at position 7, counting from the C-terminal, for the full expression of their biologic activity.
The principal physiclogic actions of CCK are stimulation of gallbladder contraction and of pancreatic enzyme secretion. There is evidence which supports a physiclogic role of CCK in the inhibition of gastric emptying, stimulation of pancreatic growth and release of pancreatic polypeptide.
Other possible actions of CCK include stimulation of insulin, glucagon, somatostatin and peptide YY release, stimulation of hepatic bile flow, intestinal motility, blood flow in the superior mesenteric artery, secretion of pepsinogen from gastric glands, and secretion of bicarbonate from the stomach and duodenum. In contrast to gastrin, CCK relaxes the lower esophageal sphincter.
In the nervous system CCK may act as a neurotransmitter or as a neuromodulator. As such, exogenous CCK has been shown to affect memory. Also levels of acetylcholine and dopamine have been affected by exogenous CCK. CCK has been implicated as well for producing the satiety effect, however, it is not clear if this is regulated by peripheral or central mechanisms.
There is considerable overlap in the biological activities elicited by gastrin and CCK. Therefore, gastrin receptor antagonists may also possess activity at the CCK receptors or vice versa.
2. Reported Developments
Four distinct chemical classes of CCK-A (peripheral CCK) receptor antagonists have been reported (see R. M. Freidinger, Medicinal Research Reviews, 9(3), 271-290 (1989)).
(1) Cyclic nucleotides, e.g. dibutyryl cyclic GMP (see N. Boilos et al., Am. J. Physiol. 242, G 161 (1982) and P. Robberecht et al., Mol. Pharmacol., 17, 268 (1982)).
(2) Amino acid derivatives, characterized by proglumide, a derivative of glutamic acid and N-acylated tryptophans, i.e. para-chlorobenzoyl-L-tryptophan (benzotript) (see W. F. Hahne et al., Proc. Natl. Acad. Sci. USA, 78: 6304 (1981) and R. T. Jensen et al., Biochem. Biophys. Acta. 76, 269 (1983)); also second generation proglumide analogues typified by Lorglumide and Loxiglumide (F. Makovec et al., Arzneim-Forsch., 37(II), 1265 (1987)). The latter two analogues have considerably better receptor affinity and selectivity.
(3) Peptide and pseudopeptide analogs based on the C-terminal end of CCK, especially analogues of CCK-8, cholecystokinin tyrosine-sulfated octapeptide Some examples are cholecystokinin-27-32-amide (M. Spanarkel et al., J. Biol. Chem. 258, 6746 (1983)) and a synthetic peptide derivative of cholecystokinin containing D-tryptophan and norleucine (M. F. Lignon et al. J. Biol. Chem. 262, 7226 (1987)).
(4) Non-peptide structures, e.g. the fermentation product asperlicin (R. S. L. Chang et al., Science 230, 177 (1985)). Subsequent medicinal chemistry done on this compound culminated in the 1,4-benzodiazepine (MK329) series having very high CCK-A affinity (B. E. Evans et al., J. Med. Chem. 31, 2235-2246 (1988)).
Structurally related compounds which retain nanomolar level potency for the CCK-A receptor have recently been reported, e.g. 3-aminobenzolactam (R. S. L. Chang and W. H. Parsons, Eur. Pat. Appl. EP 166,345 (1986), and W. H. Parsons et al., J. Med. Chem., 32, 1681-1685 (1989) and .beta.-carbolines (B. E. Evans, Eur. Pat. Appl. EP 304,233 (1988) and M. Itonaga et al., Japan. J. Pharmacol., 46, 319-324 (1988)).
Compounds selective for the peripheral gastrin receptor also possess strong affinity for the CCK-B receptor (a CCK receptor located in the CNS). Presently there are no known agents which differentiate substantially between the CCK-B receptor and the peripheral gastrin receptor. Compounds selective for gastrin generally fall into two major classes.
(1) Peptide and pseudopeptide analogs based on C-terminal amino acids of CCK or gastrin, especially CCK-4 (the C-terminal tetrapeptide of gastrin). Some examples are the pseudopeptide in which the peptide bond between leucine and aspartic acid of Boc-CCK-4 has been replaced by CH.sub.2 NH bond and has the same binding affinity as Boc-CCK-4 but has no agonist activity (J. Martinez et al., J. Med. Chem., 28, 1874, (1985)).
Other analogues of CCK-4 containing partial retro-inverso modifications have been demonstrated to bind strongly to the gastrin receptor and block the effects of gastrin in the rat (in vivo) (M. Rodriguez et al., J. Med. Chem., 30, 758-763, (1987)).
Recently some cyclic cholecystokinin analogues of CCK-8 have demonstrated selectivity for the CCK-B (CNS) receptor relative to CCK-A (peripheral ), B. Charpentier, et al., Proc. Natl. Acad. Sci. USA, 85, 1968-1972, (1988).
(2) Benzodiazepines. The 3-substituted 1,4-benzodiazepines effective as selective antagonists of CCK-A have been modified synthetically resulting in agents selective for the peripheral gastrin and CCK-B (brain) receptors, such as the Merck compound L-365,260 (V. J. Lotti and R. S. L. Chang, Eur. J. of Pharm., 162, 273-280 (1989), also M. G. Bock et al., J. Med. Chem., 32, 16-23, (1989)).
Other non-peptide, non-benzodiazepine compounds (e.g. analogs of Virginiamycin M1) have been reported to display strong binding affinity and selectively for gastrin (relative to CCK-A) (Y.-K. T. Lam et al., U.S. Pat. No. 4,762,923 (1988)).
Tetrahydropyridoindoles are reported to be active as gastrin and cholecystokinin antagonists in pending U.S. application Ser. No. 07/542,495, attorney docket no. A0135, filed on Jun. 21, 1990, now abandoned, and U.S. application Ser. No.: 07/573,514, attorney Docket No.: A0135A, filed Aug. 24, 1990, now U.S. Pat. No. 5,162,336, assigned to the same assignee as the present invention.
The present invention relates to novel N-arylcarbamoyl proline analogues which are useful as cholecystokinin and gastrin antagonists.